CA2744152A1 - Inhibitors of diacylglycerol acyltransferase - Google Patents
Inhibitors of diacylglycerol acyltransferase Download PDFInfo
- Publication number
- CA2744152A1 CA2744152A1 CA2744152A CA2744152A CA2744152A1 CA 2744152 A1 CA2744152 A1 CA 2744152A1 CA 2744152 A CA2744152 A CA 2744152A CA 2744152 A CA2744152 A CA 2744152A CA 2744152 A1 CA2744152 A1 CA 2744152A1
- Authority
- CA
- Canada
- Prior art keywords
- carboxylic acid
- ethyl
- carbonyl
- amino
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000003112 inhibitor Substances 0.000 title description 11
- 108010001348 Diacylglycerol O-acyltransferase Proteins 0.000 title description 5
- 102000002148 Diacylglycerol O-acyltransferase Human genes 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 143
- 150000003839 salts Chemical class 0.000 claims abstract description 45
- -1 haloloweralkyl Chemical group 0.000 claims description 89
- 239000002253 acid Substances 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 125000005907 alkyl ester group Chemical group 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- WANQRFBUYIQKFK-UHFFFAOYSA-N tert-butyl 4-[5-[(4-chloro-1-benzothiophene-2-carbonyl)amino]pyridin-2-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C(N=C1)=CC=C1NC(=O)C1=CC2=C(Cl)C=CC=C2S1 WANQRFBUYIQKFK-UHFFFAOYSA-N 0.000 claims description 18
- ZRQFAPVDBTWLEI-UHFFFAOYSA-N 4-[4-[5-[(4-chloro-1-benzothiophene-2-carbonyl)amino]pyridin-2-yl]piperazin-1-yl]-2,2-dimethyl-4-oxobutanoic acid Chemical compound C1CN(C(=O)CC(C)(C)C(O)=O)CCN1C(N=C1)=CC=C1NC(=O)C1=CC2=C(Cl)C=CC=C2S1 ZRQFAPVDBTWLEI-UHFFFAOYSA-N 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 15
- 229910052757 nitrogen Chemical group 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical group OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 claims description 10
- 239000005711 Benzoic acid Substances 0.000 claims description 9
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 239000011593 sulfur Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- MHJADBJNRMTDHI-UHFFFAOYSA-N 1-ethyl-4-methylindole-2-carboxylic acid Chemical compound C1=CC=C2N(CC)C(C(O)=O)=CC2=C1C MHJADBJNRMTDHI-UHFFFAOYSA-N 0.000 claims description 5
- PLXSTIPOOXOJGU-UHFFFAOYSA-N 2-(piperazine-1-carbonyl)cyclopentane-1-carboxylic acid Chemical compound OC(=O)C1CCCC1C(=O)N1CCNCC1 PLXSTIPOOXOJGU-UHFFFAOYSA-N 0.000 claims description 5
- ZXVJCGPNCXIZLN-UHFFFAOYSA-N 4-(piperazine-1-carbonyl)cyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1C(=O)N1CCNCC1 ZXVJCGPNCXIZLN-UHFFFAOYSA-N 0.000 claims description 5
- WVUXHDNUHWDIKB-DEOSSOPVSA-N 4-[(3s)-3-[4-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]phenoxy]pyrrolidin-1-yl]benzoic acid Chemical compound C([C@@H](C1)OC2=CC=C(C=C2)NC(=O)C=2N(CC)C=3C=CC=C(C=3C=2)OCC)CN1C1=CC=C(C(O)=O)C=C1 WVUXHDNUHWDIKB-DEOSSOPVSA-N 0.000 claims description 5
- BOYBTBKKHLEPFD-UHFFFAOYSA-N benzyl 4-(piperazine-1-carbonyl)cyclohexane-1-carboxylate Chemical compound C1CC(C(=O)N2CCNCC2)CCC1C(=O)OCC1=CC=CC=C1 BOYBTBKKHLEPFD-UHFFFAOYSA-N 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- AMNGBHKKUGMHDI-UHFFFAOYSA-N 1-ethyl-n-[6-[2-methoxyethyl(methyl)amino]pyridin-3-yl]-5-(trifluoromethoxy)indole-2-carboxamide Chemical compound C=1C2=CC(OC(F)(F)F)=CC=C2N(CC)C=1C(=O)NC1=CC=C(N(C)CCOC)N=C1 AMNGBHKKUGMHDI-UHFFFAOYSA-N 0.000 claims description 4
- FLPOVELHQSTQKA-UHFFFAOYSA-N 4-[4-[4-[(7-methoxy-3-methyl-1h-indole-2-carbonyl)amino]phenyl]piperazin-1-yl]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N1C=2C(OC)=CC=CC=2C(C)=C1C(=O)NC(C=C1)=CC=C1N1CCN(C(=O)CC(C)(C)C(O)=O)CC1 FLPOVELHQSTQKA-UHFFFAOYSA-N 0.000 claims description 4
- IWZDDBJDSAIODB-UHFFFAOYSA-N 2-(piperidine-1-carbonyl)cyclopentane-1-carboxylic acid Chemical compound OC(=O)C1CCCC1C(=O)N1CCCCC1 IWZDDBJDSAIODB-UHFFFAOYSA-N 0.000 claims description 3
- NHYBBVCRPJJRSG-NRFANRHFSA-N 4-[(3s)-3-[4-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]phenoxy]pyrrolidin-1-yl]-2,2-dimethyl-4-oxobutanoic acid Chemical compound C=1C=2C(OCC)=CC=CC=2N(CC)C=1C(=O)NC(C=C1)=CC=C1O[C@H]1CCN(C(=O)CC(C)(C)C(O)=O)C1 NHYBBVCRPJJRSG-NRFANRHFSA-N 0.000 claims description 3
- YAVUNRHXIJSNGZ-UHFFFAOYSA-N 4-[4-[4-[(4,5-dichloro-1-ethylindole-2-carbonyl)amino]phenyl]piperazin-1-yl]-2,2-dimethyl-4-oxobutanoic acid Chemical compound C=1C2=C(Cl)C(Cl)=CC=C2N(CC)C=1C(=O)NC(C=C1)=CC=C1N1CCN(C(=O)CC(C)(C)C(O)=O)CC1 YAVUNRHXIJSNGZ-UHFFFAOYSA-N 0.000 claims description 3
- OXSSDSAVLVULAO-UHFFFAOYSA-N 4-[4-[5-[(4,5-dichloro-1-ethylindole-2-carbonyl)amino]pyridin-2-yl]piperazin-1-yl]-2,2-dimethyl-4-oxobutanoic acid Chemical compound C=1C2=C(Cl)C(Cl)=CC=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N1CCN(C(=O)CC(C)(C)C(O)=O)CC1 OXSSDSAVLVULAO-UHFFFAOYSA-N 0.000 claims description 3
- ONNIQKISGPUDJA-UHFFFAOYSA-N 4-[4-[5-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]pyridin-2-yl]piperazin-1-yl]-2,2-dimethyl-4-oxobutanoic acid Chemical compound C=1C=2C(OCC)=CC=CC=2N(CC)C=1C(=O)NC(C=N1)=CC=C1N1CCN(C(=O)CC(C)(C)C(O)=O)CC1 ONNIQKISGPUDJA-UHFFFAOYSA-N 0.000 claims description 3
- FYOWTZPCCQWRFB-UHFFFAOYSA-N 4-[4-[5-[(5-bromo-1-benzothiophene-2-carbonyl)amino]pyridin-2-yl]piperazin-1-yl]-2,2-dimethyl-4-oxobutanoic acid Chemical compound C1CN(C(=O)CC(C)(C)C(O)=O)CCN1C(N=C1)=CC=C1NC(=O)C1=CC2=CC(Br)=CC=C2S1 FYOWTZPCCQWRFB-UHFFFAOYSA-N 0.000 claims description 3
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- XKOMNLKTFULJEY-DHIUTWEWSA-N (1r,2r)-2-[4-[4-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]phenyl]piperazine-1-carbonyl]cyclopentane-1-carboxylic acid Chemical compound C=1C=2C(OCC)=CC=CC=2N(CC)C=1C(=O)NC(C=C1)=CC=C1N(CC1)CCN1C(=O)[C@@H]1CCC[C@H]1C(O)=O XKOMNLKTFULJEY-DHIUTWEWSA-N 0.000 claims description 2
- NPGSNGXSGAJDEP-UHFFFAOYSA-N 2-cyclohexyl-4-oxo-2-piperazin-1-ylbutanoic acid Chemical compound C1CNCCN1C(CC=O)(C(=O)O)C1CCCCC1 NPGSNGXSGAJDEP-UHFFFAOYSA-N 0.000 claims description 2
- SMHQZIFZMIBTIY-UHFFFAOYSA-N 5-chloro-n-[6-[cyclopropyl(methyl)amino]pyridin-3-yl]-1-ethylindole-2-carboxamide Chemical compound C=1C2=CC(Cl)=CC=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N(C)C1CC1 SMHQZIFZMIBTIY-UHFFFAOYSA-N 0.000 claims description 2
- 125000005055 alkyl alkoxy group Chemical group 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
- KCUNWYMCPOOKCY-IBGZPJMESA-N n-[6-[[(3s)-1-(tert-butylcarbamoyl)pyrrolidin-3-yl]amino]pyridin-3-yl]-1-ethyl-4-methylindole-2-carboxamide Chemical compound C=1C2=C(C)C=CC=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N[C@H]1CCN(C(=O)NC(C)(C)C)C1 KCUNWYMCPOOKCY-IBGZPJMESA-N 0.000 claims description 2
- ZSKGQRPHVHCUPB-UHFFFAOYSA-N tert-butyl 4-[5-[(1-ethyl-4,6-dimethoxyindole-2-carbonyl)amino]pyridin-2-yl]piperazine-1-carboxylate Chemical compound C=1C2=C(OC)C=C(OC)C=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 ZSKGQRPHVHCUPB-UHFFFAOYSA-N 0.000 claims description 2
- IZNDPWGXKJQXEP-UHFFFAOYSA-N 1-(2-oxoethyl)-2-piperidin-1-ylcyclopentane-1-carboxylic acid Chemical group O=CCC1(C(=O)O)CCCC1N1CCCCC1 IZNDPWGXKJQXEP-UHFFFAOYSA-N 0.000 claims 2
- DGPLDFKTNYFQTQ-UHFFFAOYSA-N 4-[4-[4-[(7-methoxy-3-methyl-1h-indole-2-carbonyl)amino]phenyl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid Chemical compound N1C=2C(OC)=CC=CC=2C(C)=C1C(=O)NC(C=C1)=CC=C1N(CC1)CCN1C(=O)C1CCC(C(O)=O)CC1 DGPLDFKTNYFQTQ-UHFFFAOYSA-N 0.000 claims 2
- KBQYYFGSUVNTEY-UHFFFAOYSA-N 4-[4-[4-[(7-methoxy-3-methyl-1h-indole-2-carbonyl)amino]phenyl]piperidine-1-carbonyl]cyclohexane-1-carboxylic acid Chemical compound N1C=2C(OC)=CC=CC=2C(C)=C1C(=O)NC(C=C1)=CC=C1C(CC1)CCN1C(=O)C1CCC(C(O)=O)CC1 KBQYYFGSUVNTEY-UHFFFAOYSA-N 0.000 claims 2
- LVJVKXNZGUVQRW-XYPYZODXSA-N C1C[C@@H](C(=O)O)CC[C@@H]1C(=O)N1CCCCC1 Chemical group C1C[C@@H](C(=O)O)CC[C@@H]1C(=O)N1CCCCC1 LVJVKXNZGUVQRW-XYPYZODXSA-N 0.000 claims 2
- GTWJOFRXPOJPEL-UHFFFAOYSA-N ethyl 3-[4-[(7-methoxy-3-methyl-1h-indole-2-carbonyl)amino]phenoxy]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1OC(C=C1)=CC=C1NC(=O)C1=C(C)C2=CC=CC(OC)=C2N1 GTWJOFRXPOJPEL-UHFFFAOYSA-N 0.000 claims 2
- UNOWQHZNDSZLOU-UHFFFAOYSA-N n-[4-[4-[2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetyl]piperazin-1-yl]phenyl]-4-ethoxy-1-ethylindole-2-carboxamide Chemical compound C=1C=2C(OCC)=CC=CC=2N(CC)C=1C(=O)NC(C=C1)=CC=C1N(CC1)CCN1C(=O)CC1SC(=O)NC1=O UNOWQHZNDSZLOU-UHFFFAOYSA-N 0.000 claims 2
- QEUUVQIEPWTBDL-UHFFFAOYSA-N 1-ethyl-5-methoxy-n-[6-[2-methoxyethyl(methyl)amino]pyridin-3-yl]indole-2-carboxamide Chemical compound C=1C2=CC(OC)=CC=C2N(CC)C=1C(=O)NC1=CC=C(N(C)CCOC)N=C1 QEUUVQIEPWTBDL-UHFFFAOYSA-N 0.000 claims 1
- SHTDSBFOFATFQY-UHFFFAOYSA-N 2,2-dimethyl-4-oxo-3-piperazin-1-ylbutanoic acid Chemical group OC(=O)C(C)(C)C(C=O)N1CCNCC1 SHTDSBFOFATFQY-UHFFFAOYSA-N 0.000 claims 1
- PQYVGDNGRKIOOF-UHFFFAOYSA-N 2,2-dimethyl-4-oxo-3-piperidin-1-ylbutanoic acid Chemical group OC(=O)C(C)(C)C(C=O)N1CCCCC1 PQYVGDNGRKIOOF-UHFFFAOYSA-N 0.000 claims 1
- XKOMNLKTFULJEY-UHFFFAOYSA-N 2-[4-[4-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]phenyl]piperazine-1-carbonyl]cyclopentane-1-carboxylic acid Chemical compound C=1C=2C(OCC)=CC=CC=2N(CC)C=1C(=O)NC(C=C1)=CC=C1N(CC1)CCN1C(=O)C1CCCC1C(O)=O XKOMNLKTFULJEY-UHFFFAOYSA-N 0.000 claims 1
- WRRSKNIOOMGGMH-UHFFFAOYSA-N 2-[4-[4-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]phenyl]piperidine-1-carbonyl]cyclopentane-1-carboxylic acid Chemical compound C=1C=2C(OCC)=CC=CC=2N(CC)C=1C(=O)NC(C=C1)=CC=C1C(CC1)CCN1C(=O)C1CCCC1C(O)=O WRRSKNIOOMGGMH-UHFFFAOYSA-N 0.000 claims 1
- UODYGVCEZCTHFE-UHFFFAOYSA-N 3-methyl-2-(2-oxoethyl)-2-piperazin-1-ylbutanoic acid Chemical group O=CCC(C(C)C)(C(O)=O)N1CCNCC1 UODYGVCEZCTHFE-UHFFFAOYSA-N 0.000 claims 1
- LVJVKXNZGUVQRW-UHFFFAOYSA-N 4-(piperidine-1-carbonyl)cyclohexane-1-carboxylic acid Chemical compound C1CC(C(=O)O)CCC1C(=O)N1CCCCC1 LVJVKXNZGUVQRW-UHFFFAOYSA-N 0.000 claims 1
- VRWKTDOYQKJOPX-UHFFFAOYSA-N 4-[4-[5-[(1-ethyl-4-methoxyindole-2-carbonyl)amino]pyridin-2-yl]piperazine-1-carbonyl]cyclohexane-1-carboxylic acid Chemical compound C=1C2=C(OC)C=CC=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N(CC1)CCN1C(=O)C1CCC(C(O)=O)CC1 VRWKTDOYQKJOPX-UHFFFAOYSA-N 0.000 claims 1
- BUUFUGUKARDXGU-UHFFFAOYSA-N 4-oxo-2-phenyl-2-piperidin-1-ylbutanoic acid Chemical group C=1C=CC=CC=1C(CC=O)(C(=O)O)N1CCCCC1 BUUFUGUKARDXGU-UHFFFAOYSA-N 0.000 claims 1
- XUVOUVXBUAVCAL-UHFFFAOYSA-N 4-oxo-2-piperazin-1-ylbutanoic acid Chemical group O=CCC(C(=O)O)N1CCNCC1 XUVOUVXBUAVCAL-UHFFFAOYSA-N 0.000 claims 1
- ARPXJCWWVVEBSW-UHFFFAOYSA-N 5-(1-acetylpiperazin-2-yl)-1,3-thiazolidine-2,4-dione Chemical compound CC(=O)N1CCNCC1C1C(=O)NC(=O)S1 ARPXJCWWVVEBSW-UHFFFAOYSA-N 0.000 claims 1
- ZXVJCGPNCXIZLN-MGCOHNPYSA-N C1C[C@@H](C(=O)O)CC[C@@H]1C(=O)N1CCNCC1 Chemical group C1C[C@@H](C(=O)O)CC[C@@H]1C(=O)N1CCNCC1 ZXVJCGPNCXIZLN-MGCOHNPYSA-N 0.000 claims 1
- YKECJJQBSZRUAY-UHFFFAOYSA-N benzyl 4-[4-[5-[(1-ethyl-4-methoxyindole-2-carbonyl)amino]pyridin-2-yl]piperazine-1-carbonyl]cyclohexane-1-carboxylate Chemical compound C=1C2=C(OC)C=CC=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N(CC1)CCN1C(=O)C(CC1)CCC1C(=O)OCC1=CC=CC=C1 YKECJJQBSZRUAY-UHFFFAOYSA-N 0.000 claims 1
- LVUWSTNMCPSYOZ-SFHVURJKSA-N ethyl (3s)-3-[[5-[(1-ethyl-4-methylindole-2-carbonyl)amino]pyridin-2-yl]amino]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1NC(N=C1)=CC=C1NC(=O)C1=CC2=C(C)C=CC=C2N1CC LVUWSTNMCPSYOZ-SFHVURJKSA-N 0.000 claims 1
- GIVSKGUZUKUWMF-AWEZNQCLSA-N ethyl (3s)-3-[[5-[(4-chloro-1-benzothiophene-2-carbonyl)amino]pyridin-2-yl]amino]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CC[C@@H]1NC(N=C1)=CC=C1NC(=O)C1=CC2=C(Cl)C=CC=C2S1 GIVSKGUZUKUWMF-AWEZNQCLSA-N 0.000 claims 1
- PCQLQVZIJBOEGW-UHFFFAOYSA-N ethyl 3-[[5-[(1-ethyl-4,6-dimethoxyindole-2-carbonyl)amino]pyridin-2-yl]amino]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1NC(N=C1)=CC=C1NC(=O)C1=CC2=C(OC)C=C(OC)C=C2N1CC PCQLQVZIJBOEGW-UHFFFAOYSA-N 0.000 claims 1
- GLOXXTFQHFWBLO-UHFFFAOYSA-N ethyl 3-[[5-[(1-ethyl-5-methoxyindole-2-carbonyl)amino]pyridin-2-yl]amino]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1NC(N=C1)=CC=C1NC(=O)C1=CC2=CC(OC)=CC=C2N1CC GLOXXTFQHFWBLO-UHFFFAOYSA-N 0.000 claims 1
- IKVJVKBGHHRAOE-UHFFFAOYSA-N ethyl 3-[[5-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]pyridin-2-yl]amino]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1NC(N=C1)=CC=C1NC(=O)C1=CC2=C(OCC)C=CC=C2N1CC IKVJVKBGHHRAOE-UHFFFAOYSA-N 0.000 claims 1
- MOBWCOUYBAWJLP-UHFFFAOYSA-N ethyl 3-[[5-[(5-bromo-1-ethylindole-2-carbonyl)amino]pyridin-2-yl]amino]pyrrolidine-1-carboxylate Chemical compound C1N(C(=O)OCC)CCC1NC(N=C1)=CC=C1NC(=O)C1=CC2=CC(Br)=CC=C2N1CC MOBWCOUYBAWJLP-UHFFFAOYSA-N 0.000 claims 1
- LNOQURRKNJKKBU-UHFFFAOYSA-N ethyl piperazine-1-carboxylate Chemical group CCOC(=O)N1CCNCC1 LNOQURRKNJKKBU-UHFFFAOYSA-N 0.000 claims 1
- 125000001475 halogen functional group Chemical group 0.000 claims 1
- ZFLYDIAWYSRYSC-UHFFFAOYSA-N tert-butyl 4-[5-[(4-ethoxy-1-ethylindole-2-carbonyl)amino]pyridin-2-yl]piperazine-1-carboxylate Chemical compound C=1C=2C(OCC)=CC=CC=2N(CC)C=1C(=O)NC(C=N1)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 ZFLYDIAWYSRYSC-UHFFFAOYSA-N 0.000 claims 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical group CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims 1
- 208000008589 Obesity Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 235000020824 obesity Nutrition 0.000 abstract description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 abstract description 4
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 123
- 238000000034 method Methods 0.000 description 109
- 238000002360 preparation method Methods 0.000 description 102
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 76
- 239000000203 mixture Substances 0.000 description 62
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
- 235000019439 ethyl acetate Nutrition 0.000 description 37
- 239000002904 solvent Substances 0.000 description 37
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- 239000007787 solid Substances 0.000 description 33
- 239000000243 solution Substances 0.000 description 28
- 102100036869 Diacylglycerol O-acyltransferase 1 Human genes 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 108050004099 Diacylglycerol O-acyltransferase 1 Proteins 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000012267 brine Substances 0.000 description 22
- RMHRRMBFHGEDSR-UHFFFAOYSA-N tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(N)C=N1 RMHRRMBFHGEDSR-UHFFFAOYSA-N 0.000 description 22
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- XTVFFLAXZTWQEE-UHFFFAOYSA-N tert-butyl 4-[5-[(1-ethyl-4,5-dimethoxyindole-2-carbonyl)amino]pyridin-2-yl]piperazine-1-carboxylate Chemical compound C=1C2=C(OC)C(OC)=CC=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 XTVFFLAXZTWQEE-UHFFFAOYSA-N 0.000 description 1
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- PCOYQSVLYLCIOX-UHFFFAOYSA-N tert-butyl 4-[5-[(1-ethyl-4-propoxyindole-2-carbonyl)amino]pyridin-2-yl]piperazine-1-carboxylate Chemical compound C=1C=2C(OCCC)=CC=CC=2N(CC)C=1C(=O)NC(C=N1)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 PCOYQSVLYLCIOX-UHFFFAOYSA-N 0.000 description 1
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- XJPYQBXFKYZXTL-UHFFFAOYSA-N tert-butyl 4-[5-[[1-ethyl-4-(trifluoromethyl)indole-2-carbonyl]amino]pyridin-2-yl]piperazine-1-carboxylate Chemical compound C=1C2=C(C(F)(F)F)C=CC=C2N(CC)C=1C(=O)NC(C=N1)=CC=C1N1CCN(C(=O)OC(C)(C)C)CC1 XJPYQBXFKYZXTL-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
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- Health & Medical Sciences (AREA)
- Diabetes (AREA)
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- Veterinary Medicine (AREA)
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Indole Compounds (AREA)
Applications Claiming Priority (3)
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US11946708P | 2008-12-03 | 2008-12-03 | |
US61/119,467 | 2008-12-03 | ||
PCT/US2009/064971 WO2010065310A1 (en) | 2008-12-03 | 2009-11-18 | Inhibitors of diacylglycerol acyltransferase |
Publications (1)
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CA2744152A1 true CA2744152A1 (en) | 2010-06-10 |
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Family Applications (1)
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CA2744152A Abandoned CA2744152A1 (en) | 2008-12-03 | 2009-11-18 | Inhibitors of diacylglycerol acyltransferase |
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US8153644B2 (en) * | 2007-05-22 | 2012-04-10 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
US8115011B2 (en) | 2007-05-22 | 2012-02-14 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
US8211884B2 (en) * | 2008-08-06 | 2012-07-03 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
JP4900361B2 (ja) * | 2008-10-21 | 2012-03-21 | ソニー株式会社 | 画像処理装置、画像処理方法およびプログラム |
US8324385B2 (en) * | 2008-10-30 | 2012-12-04 | Madrigal Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
EP2378878A4 (en) * | 2008-12-17 | 2012-08-01 | Via Pharmaceuticals Inc | INHIBITORS OF DIACYLGLYCEROL ACYLTRANSFERASE |
PA8854101A1 (es) | 2008-12-18 | 2010-07-27 | Ortho Mcneil Janssen Pharm | Derivados de imidazol bicíclicos sustituidos como moduladores de gamma secretasa |
SG173510A1 (en) | 2009-02-06 | 2011-09-29 | Ortho Mcneil Janssen Pharm | Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators |
TWI461425B (zh) | 2009-02-19 | 2014-11-21 | Janssen Pharmaceuticals Inc | 作為伽瑪分泌酶調節劑之新穎經取代的苯并唑、苯并咪唑、唑并吡啶及咪唑并吡啶衍生物類 |
AU2010262036B2 (en) | 2009-05-07 | 2014-10-30 | Cellzome Limited | Novel substituted indazole and aza-indazole derivatives as gamma secretase modulators |
WO2011006903A1 (en) | 2009-07-15 | 2011-01-20 | Ortho-Mcneil-Janssen Pharmaceuticals, Inc | Substituted triazole and imidazole derivatives as gamma secretase modulators |
WO2011031628A1 (en) | 2009-09-14 | 2011-03-17 | Schering Corporation | Inhibitors of diacylglycerol acyltransferase |
CA2784769A1 (en) | 2010-01-15 | 2011-07-21 | Janssen Pharmaceuticals, Inc. | Novel substituted triazole derivatives as gamma secretase modulators |
MX2013010970A (es) | 2011-03-24 | 2013-10-17 | Cellzome Ltd | Novedosos derivados de triazolil piperazina y triazolil piperidina sustituidos como moduladores de gamma-secretasa. |
ES2555167T3 (es) | 2011-07-15 | 2015-12-29 | Janssen Pharmaceuticals, Inc. | Nuevos derivados de indol sustituidos como moduladores de gamma secretasa |
SG11201407051XA (en) | 2012-05-16 | 2014-11-27 | Janssen Pharmaceuticals Inc | Substituted 3, 4 - dihydro - 2h - pyrido [1, 2 -a] pyrazine - 1, 6 - dione derivatives useful for the treatment of (inter alia) alzheimer's disease |
WO2014096212A1 (en) | 2012-12-20 | 2014-06-26 | Janssen Pharmaceutica Nv | NOVEL TRICYCLIC 3,4-DIHYDRO-2H-PYRIDO[1,2-α]PYRAZINE-1,6-DIONE DERIVATIVES AS GAMMA SECRETASE MODULATORS |
AU2014206834B2 (en) | 2013-01-17 | 2017-06-22 | Janssen Pharmaceutica Nv | Novel substituted pyrido-piperazinone derivatives as gamma secretase modulators |
US10562897B2 (en) | 2014-01-16 | 2020-02-18 | Janssen Pharmaceutica Nv | Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators |
CN116096704A (zh) | 2020-06-24 | 2023-05-09 | 皮姆维制药公司 | 用于治疗癌症的组合疗法 |
KR20230079427A (ko) * | 2020-10-08 | 2023-06-07 | 머크 샤프 앤드 돔 엘엘씨 | 신규 디아실글리세리드 o-아실트랜스퍼라제 2 억제제로서의 옥스인돌 유도체의 제조 |
WO2024199387A1 (zh) * | 2023-03-30 | 2024-10-03 | 微境生物医药科技(上海)有限公司 | 作为DGKζ抑制剂的化合物 |
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US3250771A (en) * | 1962-12-17 | 1966-05-10 | Geigy Chem Corp | 5-monocarbocyclic aryl-n-lower alkyl-2-pyrrolidine carboxylic acid, esters, amides and derivatives thereof |
DE2337461A1 (de) * | 1973-07-24 | 1975-02-06 | Boehringer Mannheim Gmbh | Neue indolderivate und verfahren zu deren herstellung |
US4066654A (en) * | 1975-04-16 | 1978-01-03 | G. D. Searle & Co. | 1-triarylalkyl-4-phenyl-4-piperidine carboxylic acids and derivatives |
US6495558B1 (en) * | 1999-01-22 | 2002-12-17 | Amgen Inc. | Kinase inhibitors |
US6756374B2 (en) * | 2001-01-22 | 2004-06-29 | Hoffmann-La Roche Inc. | Diaminothiazoles having antiproliferative activity |
NZ531440A (en) | 2001-08-31 | 2005-10-28 | Aventis Pharma Gmbh | Diaryl cycloalkyl derivatives, method for producing the same and the use thereof as PPAR activators |
CA2497901A1 (en) | 2002-09-06 | 2004-03-18 | Takeda Pharmaceutical Company Limited | Furan or thiophene derivative and medicinal use thereof |
MXPA05005425A (es) * | 2002-11-22 | 2005-11-23 | Japan Tobacco Inc | Heterociclos que contienen nitrogeno, biciclicos, fusionados. |
US20090215779A1 (en) | 2005-06-11 | 2009-08-27 | Roger John Butlin | Oxadiazole derivatives as dgat inhibitors |
US7714126B2 (en) * | 2005-11-28 | 2010-05-11 | Via Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
WO2008099221A1 (en) * | 2007-02-15 | 2008-08-21 | Prosidion Limited | Amide and urea derivatives for the treatment of metabolic diseases |
CA2686951C (en) | 2007-05-22 | 2016-03-22 | Via Pharmaceuticals, Inc. | Diacylglycerol acyltransferase inhibitors |
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2009
- 2009-11-18 CA CA2744152A patent/CA2744152A1/en not_active Abandoned
- 2009-11-18 WO PCT/US2009/064971 patent/WO2010065310A1/en active Application Filing
- 2009-11-18 JP JP2011539569A patent/JP2012510515A/ja not_active Withdrawn
- 2009-11-18 US US12/621,109 patent/US8124766B2/en not_active Expired - Fee Related
- 2009-11-18 CN CN2009801482136A patent/CN102239165A/zh active Pending
- 2009-11-18 EP EP09830855A patent/EP2367817A4/en not_active Withdrawn
- 2009-11-18 AU AU2009322774A patent/AU2009322774A1/en not_active Abandoned
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2011
- 2011-05-16 IL IL212916A patent/IL212916A0/en unknown
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EP2367817A4 (en) | 2012-05-09 |
JP2012510515A (ja) | 2012-05-10 |
WO2010065310A1 (en) | 2010-06-10 |
US8124766B2 (en) | 2012-02-28 |
AU2009322774A1 (en) | 2011-06-30 |
EP2367817A1 (en) | 2011-09-28 |
US20100145047A1 (en) | 2010-06-10 |
CN102239165A (zh) | 2011-11-09 |
IL212916A0 (en) | 2011-07-31 |
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